A group of lymphocytes called natural killer (NK) cells can kill several kinds of cells almost indiscriminately. NK cells serve an important function in the immune surveillance of virus-infected cells and cancer cells. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize surface molecules called major histocompatibility complex class I (MHC class I). A major goal of this project is to define the molecular basis of MHC class I recognition by the inhibitory receptors on NK cells and how recognition of MHC class I by the receptor results in a negative signal transmitted to the NK cell. Although NK cells serve useful functions in immune responses against certain viruses and parasites, they are also dangerous, as they exhibit potent killing activity. Therefore, the mechanisms in place to prevent killing of normal cells by NK cells serve an essential function. It is important to understand how such regulation of NK activity is achieved. In addition, the regulation of NK cell activity by inhibitory receptors serves as a model to study other receptor systems that use a similar mode of negative regulation. The experiments carried out under this project have determined the specificity of several inhibitory receptors on human NK cells. NK cells express a family of related molecules called killer cell immunoglobulin-like receptors (KIR). Three members of the KIR family are specific for HLA-C. Crucial amino acids that determine the KIR specificity for HLA-C were identified. KIR molecules exert their inhibitory action by recruiting a tyrosine phophatase enzyme through interactions with the KIR cytoplasmic domain. Crucial amino acids that determine specific binding of the tyrosine phophatase were also identified. The definition of this amino acid sequence motif in KIR, called immunoreceptor tyrosine-based inhibition motif (ITIM), has led to the identification of a large family of inhibitory receptors that regulate the activation of many different types of cells. Regulation of cellular responses through this type of negative signaling has turned out to be much more prevalent than anticipated. - Cell adhesion, cytotoxicity, HLA-C, human leukocyte antigen (HLA), inhibitory receptor, natural killer (NK) cell, signal transduction